调控剪接异常与许多人类疾病有关，了解转录剪接基于的遗传变异对于剖析癌症的分子机制至关重要。我们的研究目标是全面功能解析癌症剪接定量性状位点（sQTLs），并重点阐明它在结直肠癌（CRC）机制中的独特作用。首先，我们进行了全面的sQTL分析，以寻找在TCGA的33种癌症类型中控制mRNA剪接的遗传变异，并在我们的154例CRC组织中进行了独立验证。然后，我们进行了大规模多中心多种族病例对照研究（34,585例病例和76,023例对照），检测这些sQTLs与CRC风险的关联性。我们还进行了一系列体内外生物学实验，以研究候选sQTLs和靶基因的潜在机制。sQTL的分子特征揭示了它在癌症易感性中的独特作用。肿瘤特异性sQTL进一步显示了对癌症发展的更好响应。此外，功能合理的多基因风险评分突出显示了sQTL在CRC预测中的潜力。通过大规模人群研究的补充，我们发现一个多民族相关的sQTL rs61746794的风险等位基因（T）在中国人群（OR=1.20，95% CI=1.12-1.29，P=8.82×10-7）和欧洲人群（OR=1.11，95% CI=1.07-1.16，P=1.13×10-7）中显著增加了CRC的风险。rs61746794-T通过RBP PRPF8介导的PRMT7外显子16剪接而增加了规范PRMT7亚型（PRMT7-V2）的水平。PRMT7-V2的过表达显著增强了CRC细胞和异种移植瘤的生长，与PRMT7-V1相比。从机制上讲，PRMT7-V2作为一个表观遗传学编码器，催化H4R3和H3R2的精氨酸甲基化，进而调节多种生物过程，包括YAP、AKT和KRAS信号通路。选择性的PRMT7抑制剂SGC3027对人类CRC细胞具有抗肿瘤效应。 我们的研究提供了有关sQTL的信息资源，并深入了解将剪接变异与癌症风险相关的调控机制，为生物标记物和治疗靶点提供了见解。版权所有 © 2023 AGA Institute。由Elsevier Inc.出版。保留所有权利。

Dysregulation of alternative splicing is implicated in many human diseases and understanding the genetic variation underlying transcript splicing is essential to dissect the molecular mechanisms of cancers. We aimed to provide a comprehensive functional dissection of splicing quantitative trait loci (sQTLs) in cancer and focus on elucidating its distinct role in colorectal cancer (CRC) mechanisms.Firstly, we performed a comprehensive sQTL analysis to identify genetic variants that control mRNA splicing across 33 cancer types from TCGA and independently validated in our 154 CRC tissues. Then, large-scale, multicenter, multiethnic case-control studies (34,585 cases and 76,023 controls) were conducted to examine the association of these sQTLs with CRC risk. A series of biological experiments in vitro and in vivo were performed to investigate the potential mechanisms of the candidate sQTLs and target genes.The molecular characterization of sQTL revealed its distinct role in cancer susceptibility. Tumor-specific sQTL further showed better response to cancer development. Besides, functionally informed polygenetic risk score highlighted the potentiality of sQTLs in the CRC prediction. Complemented by large-scale population studies, we identified that the risk allele (T) of a multi-ancestry-associated sQTL rs61746794 significantly increased the risk of CRC in Chinese populations (OR=1.20, 95% CI=1.12-1.29, P=8.82×10-7) and European populations (OR=1.11, 95% CI=1.07-1.16, P=1.13×10-7). rs61746794-T facilitated PRMT7 exon 16 splicing mediated by the RBP PRPF8, thus increasing the level of canonical PRMT7 isoform (PRMT7-V2). Overexpression of PRMT7-V2 significantly enhanced the growth of CRC cells and xenograft tumors, compared with PRMT7-V1. Mechanistically, PRMT7-V2 functions as an epigenetic writer that catalyzes the arginine methylation of H4R3 and H3R2, subsequently regulating diverse biological processes, including YAP, AKT, and KRAS pathway. A selective PRMT7 inhibitor, SGC3027, exhibited antitumor effects on human CRC cells.Our study provide an informative sQTLs resource and insights into the regulatory mechanisms linking splicing variants to cancer risk, serving as biomarkers and therapeutic targets.Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.